The goal of this proposal is to determine how ApoE polymorphisms modify comprehensive maps and subnetworks of protein complexes that are central players in the dysfunction occurring Alzheimer?s disease (AD). We will use the emerging power of quantitative network proteomics in the Emili laboratory combined with proximity profiling to systematically characterize the major protein assemblies that occur in a classic disease model of tauopathy. This research will be propelled by discoveries from the Wolozin laboratory demonstrating that a dynamic network of protein interactions drives tau biology and changes with the course of disease. The work will be further informed by cross-referencing key network members to large genetics and genomics datasets focused on AD risk, neuropathological outcomes and human brain expression data to enable prioritization of network members exhibiting disease-linked gene-gene interactions. These advanced interactome screening technologies are uniquely suited for unbiased interrogations of disease-related protein networks in the brain. We hypothesize that tau and RNA binding protein interactomes exhibit a progressive evolution with disease progression in tauopathy, and that the structure of the interactomes is modified by genetic risk factors for AD. Aim 1 will determine how APOE alleles modify neuronal interactomes with disease progression. We will cross PS19 P301S tau mice with mice carrying humanized ApoE3 or ApoE4, and compare protein-protein interaction networks for tau and the RNA binding proteins TIA1 (which interacts with pathological tau) and G3BP (which does not interact with pathological tau). Aim 2 will determine how APOE alleles modify responses to propagated pathological tau. We will compare how propagation of different tau strains changes the proteins that interact with pathological tau, and how expression of specific ApoE isoforms modify the pattern of tau propagation and the nature of the resulting tau interactomes. Aim 3 will determine how reduction of key protein interactors modifies AD-related networks, and disease progression in tauopathy. This work will examine the how reducing key network components modifies related interactome networks and disease progression in PS19xApoE3 or E4 mice under conditions of normal disease progression or accelerated progression induced by tau propagation.